The present invention relates to a composition for transdermal administration of a cytokine. The composition includes a conjugate composed of a cytokine and at least one fatty acid moiety covalently attached to the cytokine.
The routine administration of therapeutic proteins and peptides is hindered by the lack of a reliable and convenient mode of delivery. The oral route is often impractical due to the digestion of proteins in the gastrointestinal tract. Parenteral administration is an alternative, although frequent injections are required due to the short half-life of peptides and this can decrease patient compliance.
Other potential routes of administration for proteins include nasal, pulmonary, rectal, vaginal, ocular and transdermal. The transdermal route offers some advantages in that the skin has low proteolytic activity, so that metabolism of the protein during transit through the skin is minimized thereby improving bioavailability.
One problem with transdermal administration of proteins and peptides is that they may exhibit very low permeability through the skin due to their hydrophilicity and high molecular weight. One approach to overcoming the low skin permeability is directed to temporarily compromising the integrity or physicochemical characteristics of the skin to enhance skin penetration, e.g., using a skin penetration enhancer, employing ultrasonic vibration, removing the epithelial layer by suction or employing an electric current (iontophoresis). These approaches have demonstrated the feasibility of transdermal administration of proteins and peptides, however are associated with skin irritation and/or other disadvantages.
Accordingly, it is an object of the invention to provide a composition for administration of a protein or peptide transdermally. More specifically, it is an object of the invention to provide a composition for transdermal administration of a cytokine.
In one aspect, the invention includes a pharmaceutical composition for dermal or transdermal administration of a cytokine. The composition includes a conjugate composed of a cytokine and at least one fatty acid moiety having between 12-24 carbon atoms covalently attached to the cytokine. The conjugate has a substantially higher rate of skin penetration than the cytokine alone.
In one embodiment, the cytokine is an interferon or an interleukin, and in a preferred embodiment, the cytokine is interferon xcex1, interferon xcex2, interferon xcex3, interleukin 1, interleukin 2 or interleukin 13.
The fatty acid to which the cytokine is attached is a saturated fatty acid having between 12-24 carbon atoms or an unsaturated fatty acid having between 12-20 carbon atoms. In preferred embodiments of the invention, the fatty acid is palmitic acid, behenic acid or lignoceric acid.
One preferred conjugate includes interferon xcex1 as the cytokine and palmitic acid as the fatty acid.
In another aspect, the invention includes a method for dermal or transdermal administration of a cytokine. The method includes preparing a conjugate, as described above, and applying the conjugate to the skin of a subject in a pharmaceutically acceptable preparation.
In another aspect, the invention includes a method of treating an infection caused by human papilloma virus in a subject by administering topically at the site of infection, a conjugate as described above. In one embodiment of the method, the infection to be treated is genital warts and the cytokine in the conjugate is interferon xcex1.
In another aspect, the invention includes a method of enhancing an immune response to a vaccine, by administrating topically to a patient receiving a vaccine, a conjugate composed of a cytokine and, covalently attached to the cytokine, at least one fatty acid moiety having between 12-24 carbon atoms.
These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.